Drugmaker: Aptiom Monotherapy Cuts Seizures

Study supports FDA filing for expanded indication.

by John Gever John Gever,Managing Editor, MedPage Today
December 08, 2014

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

SEATTLE -- The recently approved anti-epileptic drug eslicarbazepine acetate (Aptiom), currently indicated only as adjunctive therapy, is also effective by itself, according to a manufacturer-sponsored study reported here.

In pooled data from two clinical studies that used historical controls as the comparator, eslicarbazepine monotherapy at two different dosages led to a reduced rate of loss of seizure control, which was the primary endpoint, according to Ladislav Pazdera, MD, of Oblastni Nemocnice Rychnov Nad Kneznou in the Czech Republic, and colleagues, in a poster presented at the American Epilepsy Society annual meeting.

The drug's sponsor, Sunovion Pharmaceuticals, said it had applied to the FDA for permission to market the drug as monotherapy for partial-onset seizures on the basis of these data.

When eslicarbazepine was initially approved in November 2013, the FDA restricted its use to add-on therapy, because its pivotal trials had involved patients who had remained on other anti-epileptic medications but continued to have seizures. Because the drug is related to one of those existing medications, oxcarbazepine (specifically, it's a slowly metabolized prodrug for oxcarbazepine's active metabolite), Sunovion believed it could be an effective monotherapy as well.

The two trials reported here had identical designs and enrolled a total of 332 patients, about two-thirds of them in the U.S., who showed at least four partial-onset seizures during the 8 weeks prior to screening despite use of one or two conventional medications.

They were randomized to target doses of 1,600 or 1,200 mg/day of eslicarbazepine, which were titrated upward from low starting doses while their prior medications were tapered to zero. The eslicarbazepine monotherapy period lasted 10 weeks.

For comparison, the study used data from a 2010 review of seizure control over time from previous clinical trial data. Pazdera and colleagues calculated that, on the basis of those data, 65.3% of patients would be predicted to show worsened control over the 10-week monotherapy period. Significantly lower rates of this outcome would signify a beneficial effect of eslicarbazepine monotherapy.

Both doses of the drug did indeed lead to significantly lower rates of worsened seizure control compared with the 65.3% threshold. Across the two studies, approximately 32% of patients with the 1,200-mg target dose and 22% of those with the 1,600-mg target met this endpoint (both P<0.05).

There was a significant discrepancy between the two trials, though, apparently related to where the patients were located.

The proportion of patients meeting the primary endpoint criteria was markedly greater in the trial conducted mainly in the U.S., with worsened seizure control seen in about 45% of patients in the low-dose group and 30% of the high-dose group.

In the second trial, with only 25% of patients from the U.S., rates of worsened seizure control were dramatically lower -- less than 15% at both doses. But even in the U.S.-predominant trial, outcomes according to the primary endpoint were still significantly better than the historical control rate.

The investigators said that a higher rate of obesity in the U.S. patients might have accounted for the different results. They noted a previous study indicating that obese epilepsy patients were generally less responsive to drug therapies. However, they did not perform a multivariate analysis to examine body mass index or weight category and U.S. residence as independent variables.

As expected, Pazdera and colleagues found that patients with more severe epilepsy at baseline -- as indicated by more frequent seizures and/or by more intensive treatment prior to enrollment -- were more likely to fail on eslicarbazepine monotherapy compared with participants with less severe baseline illness.

Safety data were generally consistent with those seen in the drug's previous trials. For one particular adverse effect seen with eslicarbazepine, hyponatremia, the overall incidence was less than 5%, the investigators said.

The study was funded by Sunovion and some co-authors are company employees.

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